A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous hematopoietic cell transplant recipients.

Recombinant herpes zoster (HZ) vaccines may be an alternative to the live-attenuated HZ vaccine for immunocompromised individuals. This was a phase 1/2, randomized, observer-blind, placebo-controlled study in adults with multiple myeloma, non-Hodgkin lymphoma (B- or T-cell), Hodgkin lymphoma, or acute myeloid leukemia who had undergone autologous hematopoietic stem-cell transplant 50 to 70 days earlier. Subjects (N = 121) were randomized 1:1:1:1 to receive (at months 0, 1, 3) three doses of 50 µg varicella-zoster virus glycoprotein E (gE) adjuvanted with AS01B, 3 doses of gE adjuvanted with AS01E, 1 dose of saline followed by 2 doses of gE/AS01B, or 3 doses of saline. One month after the last dose (6 months after transplant), frequencies of CD4(+) T cells expressing ≥2 activation markers after induction with gE and anti-gE antibody concentrations were higher with all gE/AS01 regimens than with saline. Both responses persisted up to 1 year in subjects vaccinated with gE/AS01. Immune responses were higher in the gE/AS01B 3-dose group than in the gE/AS01B 2-dose group but not higher than in the gE/AS01E 3-dose group. One serious adverse event (pneumonia) was considered vaccine related. Both formulations and both schedules were immunogenic and well tolerated in this population. This study was registered at www.clinicaltrials.gov as #NCT00920218.

Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study.

BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals are at increased risk of herpes zoster (HZ), even in the antiretroviral therapy (ART) era. Because concerns exist about the use of live-attenuated vaccines in immunocompromised individuals, a subunit vaccine may be an appropriate alternative. METHODS: This phase 1/2, randomized, placebo-controlled study evaluated the immunogenicity and safety of an investigational HZ subunit vaccine (HZ/su). Three cohorts of HIV-infected adults aged ≥18 years were enrolled: 94 ART recipients with a CD4(+) T-cell count of ≥200 cells/mm(3), 14 ART recipients with a CD4(+) T-cell count of 50-199 cells/mm(3), and 15 ART-naive adults with a CD4(+) T-cell count of ≥500 cells/mm(3). Subjects received 3 doses of HZ/su (50 µg varicella-zoster virus glycoprotein E [gE] combined with AS01B adjuvant) or 3 doses of saline at months 0, 2, and 6. RESULTS: One month after dose 3, serum anti-gE antibody concentrations and frequencies of gE-specific CD4(+) T cells were higher following HZ/su vaccination than after receipt of saline (P < .0001). Median cell-mediated immune responses peaked after dose 2. Humoral and cell-mediated immune responses persisted until the end of the study (month 18). No vaccination-related serious adverse events were reported. No sustained impact on HIV load or CD4(+) T-cell count was noted following vaccinations. CONCLUSIONS: HZ/su was immunogenic and had a clinically acceptable safety profile in HIV-infected adults. CLINICAL TRIALS REGISTRATION: NCT01165203.

Pharmacokinetics, Safety, and Tolerability Evaluation of Single and Multiple Doses of GSK3342830 in Healthy Volunteers.

This was a first-time-in-human randomized, double-blind, single-center, placebo-controlled dose-escalation study to determine the safety, tolerability, and pharmacokinetic (PK) profiles of GSK3342830 after single and repeat intravenous doses in healthy adult subjects (NCT0271424). Sixty-two subjects were enrolled: 48 subjects in part 1 (single dose) and 14 subjects in part 2 (multiple doses). Following single intravenous infusions, total systemic exposure of GSK3342830 was dose proportional over the 250- to 6000-mg dose range evaluated, whereas peak exposure was approximately dose proportional over the dose range. Following repeat intravenous infusions 3 times a day, GSK3342830 showed time invariance with no drug accumulation. Steady state was reached before day 3, and approximately 90% of GSK3342830 was excreted unchanged in urine. All 48 subjects in part 1 (100.0%) completed the study. In part 2, 9 subjects (64.3%) completed the study, and 5 subjects, all receiving GSK3342830, discontinued early (35.7%), 4 after experiencing fever, headache, and malaise, whereas 1 subject met predefined criteria for drug discontinuation because of transaminitis. GSK3342830 demonstrated PK consistent with other cephalosporin-class antibiotics but poor tolerability following multiple doses in healthy volunteers.